J. Pizarro

Ventilatory effects of prolonged systemic (CNS) hypoxia in awake goats.

Hypoxia isolated to the carotid body (CB) can induce time-dependent progressive hyperventilation (ventilatory acclimatization) in the absence of brain hypoxia. The studies reported in this paper were designed to determine if CNS hypoxia in the absence of CB hypoxia would affect ventilation over a 4 h period. In addition, the effect of 4 h of CNS hypoxia on the ventilatory responses to central chemoreceptor stimulation and to isolated CB stimulation were also determined. The studies were carried out in awake goats with CB blood gases controlled by an extracorporeal circuit while systemic (CNS) blood gases were determined independently by the level of inhaled gases. Systemic arterial PO2 was reduced to 40 Torr while the CB was maintained normoxic and normocapnic. Systemic arterial PCO2 was kept isocapnic. The data obtained indicate that 4 h of CNS hypoxia produced mild hyperventilation that reached a peak after 30 min of hypoxia and was sustained for the entire period of hypoxia. There was no evidence of a time-dependent progressive hyperventilation, i.e. no acclimatization. In contrast to studies in which whole body hypoxia is induced, CNS hypoxia did not result in any changes in the ventilatory responses to either central or peripheral chemoreceptor stimulation after return to normoxic conditions. These findings suggest no significant role for CNS mechanisms induced by hypoxia in ventilatory acclimatization to hypoxia in goats.

Carotid body noradrenergic sensitivity in ventilatory acclimatization to hypoxia

Norepinephrine inhibits ventilation in awake goats under normoxic, resting conditions. This inhibition is carotid body (CB) mediated and may be due to stimulation of noradrenergic receptor on the CB. Cao et al. (FASEB J. A118, 1991) recently suggested that CB noradrenergic receptors may be down regulated following 24-36 hours of hypoxic exposure in cats. Our study was aimed at determining whether a change in noradrenergic receptor sensitivity during ventilatory acclimatization to hypoxia (VAH) was responsible for the increased sensitivity of the CB to hypoxia during prolonged exposure to hypoxia in goats. We tested this hypothesis using intracarotid infusions of norepinephrine (NE) (0.5, 1.0, 5.0 micrograms.kg-1.min-1) and dopamine (DA) (1.0 micrograms.kg-1.min-1) in awake goats under control normoxic conditions, during 4 h of isocapnic hypoxia, and upon return to normoxia. NE and DA (1.0 micrograms.kg-1.min-1) both inhibited control ventilation significantly during the intracarotid infusions (56% and 62% decreases, respectively). No significant differences were found between the pre- and post-hypoxic infusions of NE and DA in normoxia. During hypoxia, inhibition of VE during NE and DA infusions was attenuated relative to control. Time-dependent change of the NE response were not apparent during the acclimatization period suggesting that a decreased carotid body chemoreceptor sensitivity to NE and DA is not responsible for the increased drive to breathe characteristic of ventilatory acclimatization to hypoxia.

Carotid body dopaminergic mechanisms are functional after acclimatization to hypoxia in goats

Ventilatory acclimatization to sustained hypoxia (VASH) is the time-dependent increase in ventilation that occurs during prolonged exposure to hypoxia. We tested the hypothesis that carotid body (CB) dopaminergic mechanisms are down-regulated during VASH, which would allow CB afferent discharge and ventilation to increase beyond the initial response to hypoxia. Domperidone (DOM; 1.0 mg.kg-1) was administered intravenously to block CB dopamine (DA) receptors after VASH was complete in awake goats. DOM caused a significant augmentation of the ventilatory response to hypoxia in acclimatized goats, failing to support the hypothesis. We conclude that inhibitory CB dopaminergic function is not significantly reduced following prolonged hypoxia, and that down-regulation of CB dopaminergic mechanisms may not be involved in VASH in the goat.

Intracarotid norepinephrine infusions inhibit ventilation in goats

Plasma norepinephrine (NE) increases from rest to exercise during normoxic exercise, and significantly more during hypoxic exercise in goats. To determine carotid body (CB) mediated effects of increased NE on ventilatory control, we investigated ventilatory responses to intracarotid NE infusions in awake, resting goats. NE was infused (0.5-5.0 micrograms.kg-1 x min-1, 2-3 min) into either a CB intact or contralateral CB-denervated carotid artery in both normoxia and hypoxia (FIO2. = 0.11). PRE-infusion measurements of arterial blood gases, blood pressure and pulmonary ventilation (VI) were compared with values 30-45 sec after beginning NE infusions at 1.0 micrograms.kg-1 x min-1. On the CB-intact side, NE infusions decreased VI by an average of 43% (P < 0.05) and increased PaCO2 4.0 +/- 0.3 mmHg (P < 0.05); ventilatory inhibition preceded an increase in arterial blood pressure. NE infusions on the CB-denervated side had no significant effects on VI or PaCO2, but still increased blood pressure to the same level as infusions on the CB-intact side. In hypoxia, NE infusions on the intact side no longer inhibited VI. NE induced VI inhibition in normoxia was similar in magnitude and time course to dopamine induced VI inhibition. Experiments were repeated following administration the alpha-adrenergic receptor antagonist, phenoxybenzamine (1 mg.kg-1, i.v.) the beta-adrenergic receptor antagonist, propranolol (1 mg.kg-1, i.v.) and the D2-dopamine receptor antagonist, domperidone (1 mg.kg-1, i.v.). Phenoxybenzamine partially blocked NE induced ventilatory depression and domperidone blocked it, but propranolol had no effect. These data indicate that NE inhibits ventilation in goats via effects on carotid chemoreceptors. NE induced inhibition is independent of changes in blood pressure or baroreceptor feedback, and appears to involve both alpha-adrenergic and D2-dopaminergic receptors.

Halothane effects on ventilatory responses to changes in intrapulmonary CO2 in geese

Experiments were conducted to test the hypothesis that halothane anesthesia functionally disrupts CO2-sensitive intrapulmonary chemoreceptors (IPC) in birds. Halothane effects on ventilatory reflexes elicited by changes in lung CO2 without extrapulmonary halothane or CO2 effects were studied in 6 anesthetized (pentobarbital, 30 mg/kg) and unidirectionally ventilated geese. Each lung was independently ventilated. Halothane was added only to gases ventilating the left lung. The left pulmonary artery was occluded to prevent changes in PCO2 or halothane concentration within the left lung from affecting arterial blood. The right lung allowed control of arterial blood gases and was vagally denervated. Left lung CO2 reflexes were observed at different levels of halothane concentration between 0 and 2% while arterial PCO2 and PO2 were held constant. Higher levels of chemical drive were necessary to initiate ventilatory movements in geese (PACO2 = 40-60 mmHg) relative to previous reports on chickens using similar experimental procedures (PaCO2 less than or equal to 30 mmHg). The amplitude of sternal movements or respiratory amplitude (RA) increased as left lung PCO2 increased from 6 to 55 mmHg, and then reached a plateau. Adding halothane (1 or 2%) to the left lung increased RA through a limited range of PCO2, but had no effect on its maximum value. Neither CO2 nor halothane in the left lung had any effect on respiratory frequency. We conclude that halothane impairs lung CO2 reflexes largely due to its effects on IPC since intrapulmonary halothane augments ventilatory activity at low, but not high intrapulmonary PCO2. Effects of halothane on IPC may play a role in the unique ventilatory effects of halothane anesthesia in intact, spontaneously breathing birds relative to mammals at equipotent anesthetic levels.

Effects of carotid body sympathetic denervation on ventilatory acclimatization to hypoxia in the goat

Our objective was to test the hypothesis that diminishing sympathetic input to the carotid body (CB) during prolonged exposure to hypoxia results in increased CB afferent activity and increased ventilatory drive. Six awake goats were studied prior to and following sectioning of the efferent sympathetic input to the CB from the superior cervical ganglion. Ventilatory responses to acute and prolonged isocapnic hypoxia (PaO2 40 Torr) and drugs (norepinephrine and dopamine, 0.5, 1.0 and 5.0 micrograms.kg-1 min-1) were collected prior to the denervation. One week and 3-4 weeks following the sympathetic denervation, the animals were restudied following the above protocol. Ventilation was significantly lower following sympathetic denervation in normoxia and during the hypoxic exposure. However, the response to acute hypoxia and the time-course of ventilatory acclimatization to hypoxia was not altered by sympathetic denervation. All doses of norepinephrine and dopamine significantly inhibited VE in a dose-dependent manner. Sympathetic denervation did not significantly alter the response to the drug infusions. The sympathetic innervation to the CB does not appear to play a role in either the acute or prolonged ventilatory responses to hypoxia in the awake goat, but may affect overall ventilation.

Intracarotid substance P infusion inhibits ventilation in the goat

Substance P (SP) has been proposed as an excitatory neuromodulator of the carotid body (CB) response to hypoxia based on data from the cat and rat. The role of SP as a CB neuromodulator in the goat is unknown. Awake (n = 14) and chloralose anesthetized goats (n = 6) were used to investigate the effects of intracarotid (IC) SP infusions (1-6 micrograms.kg-1.min-1) and bolus injections (6 micrograms kg-1) to the CB intact and denervated (CBX) sides (control) on mean ventilation (VE) and mean blood pressure (MBP). In awake goats VE was decreased by infusion or bolus SP injection at a dose of 6 micrograms.kg-1 (P < 0.05) and occurred with infusions to the intact or CBX sides. MBP was elevated with SP infusion to either the CB intact or CBX sides at all SP doses. The SP antagonist CP-96,345 (0.1 mg.kg-1, IV) blocked the decrease in VE induced by SP in normoxia and significantly increased the hypoxic ventilatory response (PaO2 = 40 torr). In anesthetized goats, IC injections of SP (1 to 6 micrograms.kg-1) reduced phrenic activity and MBP before and after CBX. In only one of five goats airway pressure was increased suggesting that bronchoconstriction was not a cause for the reduced ventilatory and phrenic activity induced by SP. Immunohistochemistry provided evidence of SP in CB nerve fibers and terminals, carotid sinus nerve axons and petrosal ganglion cells, but not in type I glomus cells. Our results do not support the view that SP is an excitatory neuromodulator of CB chemotransduction in the goat.

Intracarotid dopamine infusion does not prevent acclimatization to hypoxia

Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation that occurs during sustained exposure to hypoxia. The mechanism for VAH remains elusive. We sought to determine whether a deficiency in the availability of carotid body dopamine is the mechanism of increased ventilatory responsiveness to hypoxia during VAH in awake goats. This was based on the evidence that dopamine (DA) is primarily an inhibitory neuromodulator of carotid body (CB) function. The hypothesis was tested by intracarotid infusion of DA (5.0 micrograms kg-1 min-1) throughout VAH. VAH was not prevented by DA infusion, failing to support the hypothesis. We conclude that a deficiency in the availability of inhibitory DA release within the CB is probably not responsible for VAH. However, increased ventilatory responses to acute hypoxia after either prolonged DA infusion or hypoxia may have similar CB mechanisms.

Effects of Continuous Intracarotid Infusion of Dopamine During Long-Term Hypoxia in Awake Goats

Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation that occurs in mammals (including humans) during prolonged exposure to hypoxic environments. Goats acclimatize rapidly, reaching a ventilatory plateau within 4–6 hours of breathing hypoxic gas (Engwall & Bisgard, 1990). Evidence strongly suggests that VAH is caused by a time-dependent increase in carotid body (CB) sensitivity to hypoxia in goats (Nielsen et al, 1988). However, the mechanism for increased CB hypoxic sensitivity remains unknown.

Noradrenergic Inhibition of the Goat Carotid Body

Circulating catecholamines are considered to be respiratory stimulants in humans. This conclusion is based on studies in which intravenous infusion of norepinephrine or epinephrine produced ventilatory stimulation (Cunningham, et al., 1963; Heistad et al., 1972). Because the respiratory stimulation was diminished during hyperoxia, it was concluded that the carotid bodies were responsible for the reflex effect. Studies of norepinephrine and epinephrine in non-human species have revealed complex and sometimes conflicting effects on the carotid body and ventilation. Joels and White (1968) found tht in anesthetized and decerebrate cats, these agents stimulate ventilation, an effect eliminated by carotid sinus nerve transection. Folgering et al. (1982) found that norepinephrine and epinephrine produced transient inhibition followed by excitation of carotid chemoreceptor afferent neural discharge frequency in cats. Although similarly complex effects were found in rabbits (Matsumoto et al., 1981), Bisgard et al. (1979) found primarily inhibition but also excitation of the carotid body in dogs. More recently, the possibility of a prominent alpha-2 adrenergic inhibitory mechanism in the cat carotid body has been described (Kou et al., 1991).